Research Findings - Behavioral and Brain Development Research

Late adolescence has a number of developmental transitions, though brain maturational changes during this period are subtle and difficult to quantitatively evaluate with standard structural brain images. To date, primarily cross-sectional studies have characterized typical developmental changes during adolescence, but these processes need further description within a longitudinal framework. To assess the developmental trajectory of brain white matter, Dr. Bava and colleagues examined 22 healthy adolescents with diffusion tensor images (DTI) collected at a mean age of 17.8 years and 16-months later. Fractional anisotropy and mean, radial, and axial diffusivity were compared across the two time points. At follow-up, adolescents showed a significant change (>or=153 contiguous voxels each at p<0.01) in diffusion properties, including in bilateral superior longitudinal fasciculi, superior corona radiata, anterior thalamic radiations, and posterior limb of the internal capsule. Overall, correlations with cognitive performances suggested behavioral improvement corresponding with white matter changes. These longitudinal DTI findings support continued microstructural change in white matter during late adolescence, and suggest ongoing refinement of projection and association fibers into early adulthood. Bava S, Thayer R, Jacobus J, Ward M, Jernigan TL, Tapert SF. Longitudinal characterization of white matter maturation during adolescence. Brain Research 2010 Apr 23;1327: 38-46.

A Pilot Randomized Study of Smokeless Tobacco Use among Smokers not Interested in Quitting: Changes in Smoking Behavior and Readiness to Quit

Several prior studies suggest that smokeless tobacco use results in less carcinogenic risk than does cigarette smoking. Whether smokers will use smokeless tobacco is unclear, as is the impact of such use on long-term smoking behavior and cessation. It is equally plausible that smokeless tobacco use among smokers could either (a) increase total tobacco exposure and undermine motivation to quit or (b) decrease overall tobacco exposure, motivate smokers to quit, and enhance cessation. Either outcome is of major public health significance. Dr. Carpenter and colleagues conducted a small (N = 31), short-term (2 week) pilot study in which smokers uninterested in quitting were randomized to (a) receive Ariva or Stonewall (both spitless and smokeless tobacco lozenges) or (b) continue smoking conventional cigarettes. Ariva/Stonewall use led to a significant reduction (40%, 95% CI: 24%-55%) in cigarettes per day, no significant increases in total tobacco use (cigarettes + Ariva/Stonewall; p > .05), and significant increases in two measures of readiness to quit, either in the next month (p < .001) or within the next 6 months (p = .04), as well as significant increases in self-efficacy to quit smoking (p < .001). No such changes were found among smokers maintained on conventional cigarettes. These results suggest no deleterious effect on short-term smoking and quitting behavior among smokers who use smokeless tobacco. More broadly, this study suggests a strong need for a large prospective randomized clinical trial to more accurately assess the long-term viability of smokeless tobacco use as a method for cessation induction among unmotivated smokers. Carpenter MJ, Gray KM. A pilot randomized study of smokeless tobacco use among smokers not interested in quitting: changes in smoking behavior and readiness to quit. Nicotine Tob Res. 2010 Feb;12(2): 136-143.

EEG Spectral Phenotypes: Heritability and Association with Marijuana and Alcohol Dependence in an American Indian Community Study

Native Americans have some of the highest rates of marijuana and alcohol use and abuse, yet neurobiological measures associated with dependence on these substances in this population remain largely undescribed. The present investigation, conducted by Dr. Ehlers and colleagues, evaluated the heritability of spectral characteristics of the electroencephalogram (EEG) and their correlation with marijuana and alcohol dependence in an American Indian community. Participants (n=626) were evaluated for marijuana (MJ) and alcohol (ALC) dependence, as well as other psychiatric disorders. EEGs were collected from six cortical sites and spectral power determined in five frequency bands (delta 1.0-4.0 Hz, theta 4.0-7.5 Hz, alpha 7.5-12.0 Hz, low beta 12.0-20.0 Hz and high beta/gamma 20-50 Hz). Stepwise linear regression was used to detect correlations between MJ and ALC dependence and the spectral characteristics of the EEG using a model that took into account: age, gender, Native American Heritage (NAH) and a lifetime diagnosis of antisocial personality and/or conduct disorder (ASPD/CD). Increases in spectral power in the delta frequency range, were significantly correlated with gender (p<0.001) and marijuana dependence (p<0.003). Gender, age, NAH and ASPD/CD were all significantly (p<0.001) correlated with theta, alpha and beta band power, whereas alcohol dependence (p<0.01), gender (p<0.001), and ASPD/CD (p<0.001) were all correlated with high beta/gamma band power. These data suggest that the traits of EEG delta and high beta/gamma activity are correlated with MJ dependence and alcohol dependence, respectively, in this community sample of Native Americans. Ehlers CL, Phillips E, Gizer IR, Gilder DA, Wilhelmsen KC. EEG spectral phenotypes: heritability and association with marijuana and alcohol dependence in an American Indian community study. Drug Alcohol Depend. 2010 Jan 15;106(2-3): 101-110.

Early-onset cannabis use has been associated with later use/abuse, mental health problems (psychosis, depression), and abnormal development of cognition and brain function. During adolescence, ongoing neurodevelopmental maturation and experience shape the neural circuitry underlying complex cognitive functions such as memory and executive control. Prefrontal and temporal regions are critically involved in these functions. Maturational processes leave these brain areas prone to the potentially harmful effects of cannabis use. Dr. Jager and colleagues performed a two-site (United States and the Netherlands; pooled data) functional magnetic resonance imaging (MRI) study with a cross-sectional design, investigating the effects of adolescent cannabis use on working memory (WM) and associative memory (AM) brain function in 21 abstinent but frequent cannabis-using boys (13-19) years of age and compared them with 24 nonusing peers. Brain activity during WM was assessed before and after rule-based learning (automatization). AM was assessed using a pictorial hippocampal-dependent memory task. Cannabis users performed normally on both memory tasks. During WM assessment, cannabis users showed excessive activity in prefrontal regions when a task was novel, whereas automatization of the task reduced activity to the same level in users and controls. No effect of cannabis use on AM-related brain function was found. In adolescent cannabis users, the WM system was overactive during a novel task, suggesting functional compensation. Inefficient WM recruitment was not related to a failure in automatization but became evident when processing continuously changing information. The results seem to confirm the vulnerability of still developing frontal lobe functioning for early-onset cannabis use. Jager G, Block RI, Luijten M, Ramsey NF. Cannabis use and memory brain function in adolescent boys: A cross-sectional multicenter functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry 2010;49(6): 561-572.

Test of Association between GABRA2 (SNP rs279871) and Adolescent Conduct/Alcohol Use Disorders Utilizing a Sample of Clinic Referred Youth with Serious Substance and Conduct Problems, Controls and Available First Degree Relatives

Recent findings have linked the GABRA2 gene with antisocial personality disorder and alcohol dependence (AD) in adults and conduct disorder (CD), but not AD symptoms, in children and adolescents. Dr. Sakai and colleagues sought to replicate previous findings and test for an association between a single nucleotide polymorphism (SNP) in the GABRA2 gene (rs279871) and CD among adolescents. Adolescent patients (n=371), 13-18 years old, were recruited from a university substance abuse treatment program. Patient siblings (n=245), parents of patients (n=355), adolescent controls (n=185), siblings of controls (n=163) and parents of controls (n=263) were included in these analyses (total sample n=1582). Case-control (using only Caucasian and Hispanic probands) and family-based association tests were completed to test for association between rs279871 and several a priori CD and AD phenotypes. For case-control association tests, rs279871 was significantly associated with CD (p=0.02) but not AD phenotypes; the result did not survive strict correction for multiple testing. All family-based association tests were non-significant (CD p=0.48; CD symptom count age corrected within sex p=0.91; AD p=0.84; alcohol use disorder p=0.52). Consistent with previous findings, the results do not support the association between GABRA2 SNP rs279871 and AD in adolescents. The results also do not support an association between rs279871 and CD; the study limitations are reviewed. Sakai JT, Stallings MC, Crowley TJ, Gelhorn HL, McQueen MB, Ehringer MA. Test of association between GABRA2 (SNP rs279871) and adolescent conduct/alcohol use disorders utilizing a sample of clinic referred youth with serious substance and conduct problems, controls and available first degree relatives. Drug Alcohol Depend. 2010 Jan 15;106(2-3): 199-203.

Researchers from the multi-site (Detroit, Miami, Memphis, and Providence) Maternal Lifestyle study examined the association between prenatal cocaine exposure and postnatal environmental adversity on salivary cortisol stress reactivity in school-aged children. Subjects included 743 11-year-old children (n = 320 cocaine-exposed; 423 comparison) followed since birth in a longitudinal prospective multisite study. Saliva samples were collected to measure cortisol at baseline and after a standardized procedure to induce psychological stress. Children were divided into those who showed an increase in cortisol from baseline to post stress and those who showed a decrease or blunted cortisol response. Covariates measured included site, birth weight, maternal pre and postnatal use of alcohol, tobacco or marijuana, social class, changes in caretakers, maternal depression and psychological symptoms, domestic and community violence, child abuse, and quality of the home. With adjustment for confounding variables, cortisol reactivity to stress was more likely to be blunted in children with prenatal cocaine exposure. Children exposed to cocaine and who experienced domestic violence showed the strongest effects. The combination of prenatal cocaine exposure and an adverse postnatal environment could down regulate the hypothalamic-pituitary-adrenal axis resulting in the blunted cortisol response to stress possibly increasing risk for later psychopathology and adult disease. Lester BM, Lagasse LL, Shankaran S, Bada HS, Bauer CR, Lin RD, Abhik AR. Prenatal cocaine exposure related to cortisol stress reactivity in 11-year-old children. J Pediatr. 2010 Aug;157(2): 288-295.e1.

Sleep Problems in Children with Prenatal Substance Exposure

This study examined associations between sleep problems and prenatal exposure to cocaine, opiates, marijuana, alcohol, and nicotine in children aged 1 month to 12 years in the Maternal Lifestyle multi-site study. There were 808 participants, 374 exposed to cocaine and/or opiates, and 434 comparison subjects. Sleep problems in early, middle, and/or late childhood were assessed as composites of maternal report items. Prenatal nicotine exposure was the only unique predictor of sleep problems with adjustment for covariates, including socioeconomic status, marital status, physical abuse, prenatal medical care, and postnatal cigarette smoke exposure. Prenatal exposure to nicotine was positively associated with children's sleep problems persisting throughout the first 12 years of life. Targeting of this group of children for educational and behavioral efforts to prevent and treat sleep problems is merited given that good sleep may serve as a protective factor for other developmental outcomes. Stone KC, LaGasse LL, Lester BM, Shankaran S, Bada HS, Bauer CR, Hammond JA. Sleep problems in children with prenatal substance exposure: the maternal lifestyle study. Arch Pediatr Adolesc Med. 2010 May;164(5): 452-456.

Prenatal Cocaine Exposure, BMI and Blood Pressure at Age 9

Prenatal cocaine exposure has been linked to intrauterine growth retardation and poor birth outcomes; little is known about the effects on longer-term medical outcomes, such as overweight status and hypertension in childhood. The objective of this study was to examine the association between prenatal cocaine exposure and BMI and blood pressure at 9 years of age among children followed prospectively in the multisite longitudinal MLS study evaluating the impact of maternal lifestyle during pregnancy on childhood outcome. This analysis includes 880 children (277 cocaine exposed and 603 with no cocaine exposure) with blood pressure, height, and weight measurements at 9 years of age. Regression analyses were conducted to explore the relationship between prenatal cocaine exposure and BMI and blood pressure at 9 years of age after controlling for demographics, other drug exposure, birth weight, maternal weight, infant postnatal weight gain, and childhood television viewing, exercise, and dietary habits at 9 years. At 9 years of age, 15% of the children were prehypertensive and 19% were hypertensive; 16% were at risk for overweight status and 21% were overweight. A small percentage of women were exposed to high levels of prenatal cocaine throughout pregnancy. A higher BMI was noted in children born to these women. Path analysis used to further explore these relationships suggested that high cocaine exposure has an indirect effect on systolic and diastolic blood pressures that is mediated through its effect on BMI. High levels of in-utero cocaine exposure are a marker for elevated BMI and blood pressure among children born full term. Shankaran S, Bann CM, Bauer CR, Lester BM, Bada HS, Das A, Higgins RD, Poole WK, LaGasse LL, Hammond J, Woldt E. Prenatal cocaine exposure and BMI and blood pressure at 9 years of age. J Hypertens. 2010 Jun;28(6): 1166-1175.

Prenatal Methamphetamine Exposure and Neonatal Neurobehavioral

Outcomes in the USA and New Zealand Methamphetamine (MA) use among pregnant women is a world-wide problem, but little is known of its impact on exposed infants. The prospective, controlled longitudinal Infant Development, Environment and Lifestyle (IDEAL) study of prenatal MA exposure from birth to 36 months was conducted in the US and NZ. The US cohort has 183 exposed and 196 comparison infants; the NZ cohort has 85 exposed and 95 comparison infants. Exposure was determined by self-report and meconium assay with alcohol, marijuana, and tobacco exposures present in both groups. The NICU Neurobehavior Scale (NNNS) was administered within 5 days of life. NNNS summary scores were analyzed for exposure including heavy exposure and frequency of use by trimester and dose-response relationship with the amphetamine analyte. MA exposure was associated with poorer quality of movement, more total stress/abstinence, physiological stress, and CNS stress with more nonoptimal reflexes in NZ but not in the USA. Heavy MA exposure was associated with lower arousal and excitability. First trimester MA use predicted more stress and third trimester use more lethargy and hypotonicity. Dose-response effects were observed between amphetamine concentration in meconium and CNS stress. Across cultures, prenatal MA exposure was associated with a similar neurobehavioral pattern of under arousal, low tone, poorer quality of movement and increased stress. LaGasse LL, Wouldes T, Newman E, Smith LM, Shah RZ, Derauf C, Huestis MA, Arria AM, Della Grotta S, Wilcox T, Lester BM. Prenatal methamphetamine exposure and neonatal neurobehavioral outcomes in the USA and New Zealand. Neurotoxicol. Teratol 2010, doi:10.1016/j.ntt.2010.06.009.

Prenatal Drug Exposure: Infant and Toddler Outcomes

This paper provides a current overview of the scientific literature on the impact of maternal drug use, specifically opioid and cocaine, during pregnancy on the acute and long-term outcomes of infants and toddlers from birth through age 3 years. Emphasis with regard to opioids is placed on heroin and opioid substitutes used to treat opioid addiction, including methadone, which has long been regarded as the standard of care in pregnancy, and buprenorphine, which is increasingly being investigated and prescribed as an alternative to methadone. Controlled studies comparing methadone at high and low doses, as well as those comparing methadone with buprenorphine, are highlighted and the diagnosis and management of neonatal abstinence syndrome is discussed. Over the past two decades, attention of the scientific and lay communities has also been focused on the potential adverse effects of cocaine and crack cocaine, especially during the height of the cocaine epidemic in the United States. Herein, the findings are summarized from prospective studies comparing cocaine-exposed with non-cocaine-exposed infants and toddlers with respect to anthropometric growth, infant neurobehavior, visual and auditory function, and cognitive, motor, and language development. The potentially stigmatizing label of the so-called "crack baby" preceded the evidence now accumulating from well-designed prospective investigations that have revealed less severe sequelae in the majority of prenatally exposed infants than originally anticipated. In contrast to opioids, which may produce neonatal abstinence syndrome and infant neurobehavioral deficits, prenatal cocaine exposure appears to be associated with what has been described as statistically significant but subtle decrements in neurobehavioral, cognitive, and language function, especially when viewed in the context of other exposures and the caregiving environment which may mediate or moderate the effects. Whether these early findings may herald more significant learning and behavioral problems during school-age and adolescence when the child is inevitably confronted with increasing social and academic challenges is the subject of ongoing longitudinal research. Bandstra ES, Morrow CE, Mansoor E, Accornero VH. Prenatal drug exposure: infant and toddler outcomes. J Addict Dis. 2010 Apr;29(2): 245-258.

ERP and Response Inhibition in ADHD with and without Prenatal Alcohol Exposure

The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes. Dr. Avison and his colleagues at Wayne State School of Medicine in Detroit recorded event-related potentials (ERPs) during a Go/No-go response inhibition task in young adults with prospectively obtained histories of prenatal alcohol exposure and childhood ADHD. Regardless of prenatal alcohol exposure, participants with childhood ADHD were less accurate at inhibiting responses. However, only the ADHD group without prenatal alcohol exposure showed a markedly diminished P3 difference between No-go and Go, which may reflect a more effortful strategy related to inhibitory control at the neural processing level. This finding supports a growing body of evidence suggesting that the manifestation of idiopathic ADHD symptoms may stem from a neurophysiologic process that is different from the ADHD symptomatology associated with prenatal alcohol exposure. Individuals who have been prenatally exposed to alcohol and present with ADHD symptomatology may represent a unique endophenotype of the disorder, which may require different treatment approaches from those found to be effective with idiopathic ADHD. Burden MJ, Jacobson JL, Westerlund A, Lundahl LH, Morrison A, Dodge NC, Klorman R, Nelson CA, Avison MJ, Jacobson SW. An event-related potential study of response inhibition in ADHD with and without prenatal alcohol exposure. Alcohol Clin Exp Res 2010 Apr; 34: 617-627.

Nicotine and Metabolites in Meconium as Evidence of Maternal Cigarette Smoking during Pregnancy and Neonatal Growth Deficits

Many women continue tobacco use during pregnancy despite known adverse consequences on neonatal growth and development. Testing meconium, the first neonatal feces, for tobacco biomarkers offers objective evidence of prenatal tobacco exposure. However, relationships between the amount, frequency, and timing of cigarette smoking during gestation and tobacco biomarker meconium concentrations and neonatal outcomes are unclear. In this study by Dr. Marilyn Huestis (NIDA IRP) and her extramural colleague Dr. Rina Eiden, eighty-seven pregnant women provided detailed self-reports of daily tobacco consumption throughout pregnancy. Nicotine, cotinine, and trans-3'-hydroxycotinine were quantified in neonatal meconium by liquid chromatography-tandem mass spectrometry. Among nonsmokers, all meconium specimens were negative, whereas nearly all meconium specimens were positive if the mother self-reported tobacco use into the third trimester. Tobacco biomarker concentrations were significantly albeit weakly correlated with mean cigarettes per day in the third trimester. Reduced birth weight, gestational age, or head circumference were observed if meconium contained one or more tobacco biomarkers, but deficits did not correlate with biomarker concentrations. While previously thought to reflect second and third trimester drug exposure, meconium appears to reliably identify only third trimester drug use. While a 10 ng/g nicotine, cotinine, or trans-3'-hydroxycotinine cutoff in meconium was previously proposed to differentiate tobacco-exposed from nonexposed or passively exposed neonates, improved maternal self-reporting techniques in this cohort suggest that a lower cutoff, equivalent to the analytic limits of quantification, is more appropriate. Gray TR, Eiden RD, Leonard KE, Connors G, Shisler S, Huestis MA. Nicotine and metabolites in meconium as evidence of maternal cigarette smoking during pregnancy and predictors of neonatal growth deficits. Nicotine Tob Res. 2010 Jun;12(6): 658-664. Epub 2010 Apr 28.

Prenatal methamphetamine (MAMP) exposure is poorly reflected in neonatal meconium. Often, maternal self-reported MAMP use is not corroborated by positive results in amphetamines immunoassays of meconium, and even if initial test results are positive, they frequently are not confirmed for MAMP or amphetamine (AMP) by chromatographic analysis. The presence of the MAMP metabolites p-hydroxymethamphetamine (pOHMAMP), p-hydroxyamphetamine (pOHAMP), and norephedrine (NOREPH) in meconium may improve the identification of MAMP- and AMP-exposed neonates. In this study by Dr. Marilyn Huestis (NIDA IRP) and her extramural colleagues from the IDEAL prenatal methamphetamine study, immunoassay-positive and -negative meconium samples were subjected to liquid chromatography- tandem mass spectrometric reanalysis for these recently identified metabolites. pOHAMP and NOREPH were detected only when MAMP and/or AMP were present and thus do not appear to be promising biomarkers of prenatal MAMP exposure. pOHMAMP, in contrast, identified 6 additional neonates whose mothers reported MAMP exposure, yet had a meconium sample screened as negative; pOHMAMP was more likely to be present if maternal MAMP use continued into the third trimester. Although the pOHMAMP results for meconium samples corroborated the maternal self-reports, the confirmation rate for positive meconium screening results did not improve with the inclusion of these new biomarkers. pOHMAMP identified additional MAMP- exposed neonates; therefore, MAMP, AMP, and pOHMAMP should be included in meconium chromatographic analyses. Maximizing the identification of MAMP-exposed children requires improvement in immunoassay screening tests to reduce false-negative and false-positive results. Additional research will help clarify which AMP-related compounds, if any, contribute to unconfirmed positive results in screening tests. Furthermore, nonamphetamine compounds endogenous to the complex meconium matrix also may cross-react, making chromatographic confirmation of screening results essential. Gray TR, Kelly T, LaGasse LL, Smith LM, Derauf C, Grant P, Shah R, Arria A, Haning W, Della Grotta S, Strauss A, Lester BM, Huestis MA. New meconium biomarkers of prenatal methamphetamine exposure increase identification of affected neonates. Clin Chem 2010 May 56(5): 856-860, Epub 2010 Feb 25.

Improvement in Intelligence from 6 to 10 years in Children of Teenage Mothers

This study by Dr. Marie Cornelius and colleagues is part of a study of the long-term outcomes of cigarette smoking in teenage mothers. This study investigates change in IQ scores among 290 children born to teenage mothers and identifies social, economic, and environmental variables that may be associated with change in intelligence test performance. The children of 290 teenage mothers (72% African-American and 28% European American) were assessed with the Stanford-Binet Intelligence Scale-4th Edition at ages 6 and 10. The mean composite score at age 6 was 84.8 and 91.2 at age 10, an improvement of 6.4 points. Significant cross-sectional predictors at both ages 6 and 10 of higher Stanford-Binet Intelligence Scale scores were maternal cognitive ability, school grade, white ethnicity, and caregiver education. Having more children in the household significantly predicted lower Stanford-Binet Intelligence Scale scores at age 6. Higher satisfaction with maternal social support predicted higher Stanford-Binet Intelligence Scale scores at age 10. Change in IQ scores was not related to maternal socioeconomic status, social support, home environment, ethnicity, or family interactions. Custodial stability was associated with an improvement in IQ scores, whereas increase in caregiver depression was related to decline in IQ scores. These findings suggest that improvement in IQ scores of offspring of teenage mothers may be related to stability of maternal custody. More research is needed to determine the impact of the maturation of adolescent mothers' parenting and the role of early education on improvement in cognitive abilities. Cornelius MD, Goldschmidt L, De Genna NM, Richardson GA, Leech SL, Day R. Improvement in intelligence test scores from 6 to 10 years in children of teenage mothers. J Dev Behav Pediatr. 2010 Jun;31(5): 405-413.

Dr. Kathy Tassiopoulos and her colleagues from the Pediatric HIV/AIDS Cohort Study evaluated prenatal substance use in a cohort of 480 HIV-infected women and their uninfected children. Substance use was reported by 29%; the most common substances reported were tobacco (18%), alcohol (10%), and marijuana (7.2%). Fewer than 4% of women reported cocaine or opiate use. Substance use was more common in the first trimester (25%) than the second (17%) and third (15%) and was associated with race/ethnicity, education, birthplace, age and marital status. For 264 mother/infant pairs with meconium results, sensitivity of self-report was 86% for tobacco, 80% for marijuana and 67% for cocaine. Higher discordance between self-report and urine/blood toxicology was observed for cocaine, marijuana and opiates in a non-random subset of mothers/infants with these tests. Findings suggest reasonably complete self-reporting of substance use as confirmed by meconium analysis. Illicit substance use was low and substantially less than that reported in earlier studies of HIV-infected women, but alcohol and tobacco exposure was prevalent. Tassiopoulos K, Read JS, Brogly S, Rich K, Lester B, Spector SA, Yogev R, Seage GR 3rd. Substance use in HIV-infected women during pregnancy: self-report versus meconium analysis. AIDS Behav. 2010 Jun 8. [Epub ahead of print].

Relationships Between Markers of Vascular Dysfunction and Neurodevelopmental Outcomes in Perinatally HIV-infected Youth

Substance Use and Psychosocial Factors in High-Risk Youth Living with HIV

The purpose of this study, conducted in the Adolescent Trials Network for HIV/AIDS Interventions (ATN) was to test relationships between psychosocial factors and alcohol and illicit drug use among high-risk youth living with HIV (YLH). One hundred eighty-six high-risk youth with HIV (defined as those with a substance use problem, sexual risk problem, or medication adherence problem) were enrolled across five cities (ages 16-24). Alcohol and illicit drug use were measured with the alcohol, smoking, and substance involvement screening test and a timeline follow-back interview. Questionnaires assessed constructs from the adapted Transtheoretical Model (TTM) including a continuous measure of motivational readiness in response to criticisms of the stage component. Path analysis was utilized to fit cross-sectional data collected via computer assisted personal interviewing (baseline data from intervention study). Separate models were fit for each commonly used substance. In the previous month, 47% used alcohol, 37% used cannabis, and 9% used other illicit drugs. Path models fit the data well and accounted for 30% of the variance in alcohol use and 47% in cannabis use. Higher self-efficacy predicted lower alcohol and cannabis use, but motivational readiness was only directly related to cannabis use. A reduction in pros of substance use was indirectly related to use. Social support and psychological distress were associated with TTM constructs. Interventions focusing on improving motivation and self-efficacy for healthy behaviors may reduce substance use in YLH. Naar-King S, Kolmodin K, Parsons JT, Murphy D, ATN 004 Protocol Team, Adolescent Trials Network for HIV/AIDS Interventions. Psychosocial factors and substance use in high-risk youth living with HIV: a multi-site study. AIDS Care. 2010 Apr;22(4): 475-482.

Youth Living with HIV and Problem Substance Use: Elevated Distress is Associated with Nonadherence and Sexual Risk

The purpose of this Adolescent Trials Network for HIV/AIDS Interventions (ATN) study was to examine health risk behaviors in distressed youth living with HIV (YLH) with problem substance use. The study assessed distress, antiretroviral (ARV) adherence, and unprotected sex in a racially and geographically diverse sample of 122 YLH. A total of 87% of distressed YLH reported significantly more past-month ARV nonadherence (odds ratio [OR] = 7.15) and were more likely to have unprotected sex under the influence (OR = 5.14) than nondistressed youth. Distressed YLH with problem substance use may benefit from interventions to improve adherence and to decrease sexual risk, especially while under the influence of drugs. Nugent NR, Brown LK, Belzer M, Harper GW, Nachman S, Naar-King S, Adolescent Trials Network for HIV/AIDS Interventions. Youth living with HIV and problem substance use: elevated distress is associated with nonadherence and sexual risk. J Int Assoc Physicians AIDS Care (Chic Ill). 2010 Mar-Apr;9(2): 113-115.

Transition of Adolescents with HIV to Adult Care in the ATN

The transition process from pediatric to adult health care for adolescents with chronic diseases is always challenging and can be even more so for adolescents with HIV disease. The purpose of this study was to describe characteristics and current practices surrounding the transition of adolescents from the clinics of the Adolescent Trials Network for HIV/AIDS Interventions (ATN) to adult medical care. This report focuses on the processes of transition, perceived barriers and facilitators, and anecdotal reports of successes and failures. Practice models used to assist adolescents during transition to adult medical care are described. Interviews were conducted with 19 key informants from 14 Adolescent Trials Network clinics. Findings revealed no consistent definition of "successful" transition, little consensus among the sites regarding specific elements of a transition program, and a lack of mechanisms to assess outcomes. Sites that viewed transition as a process rather than an event consistently described more structured program elements. Gilliam PP, Ellen JM, Leonard L, Kinsman S, Jevitt CM, Straub DM. Transition of adolescents with HIV to adult care: Characteristics and current practices of the Adolescent Trials Network for HIV/AIDS Interventions. J Assoc Nurses AIDS Care. 2010 Jun 9. [Epub ahead of print].

Identification of HIV-Infected 12- to 24-Year-Old Men and Women in 15 US Cities Through Venue-Based Testing

Racial and ethnic minority women and men who have sex with men (WSM and MSM) compose the majority of new HIV cases among adolescents and young adults. The purpose of this study was to test whether "venue-based testing" could identify human immunodeficiency virus (HIV) infection in US youth, 12 to 24 years of age, who were otherwise not aware of their infection. Venues were selected in communities surrounding the 15 Adolescent Trials Network for HIV/AIDS Interventions (ATN) clinical sites to take part in the study over a 3-month period. At each venue, ATN sites recruited 20 to 30 English- or Spanish-speaking at-risk youth (12 to 24 years of age), resulting in a total of 1217 study participants, including 611 MSM and 606 WSM. Intervention Venue-based HIV testing had two components: An anonymous audio computer-assisted self-administered interview and an anonymous HIV antibody assay. The prevalence of HIV infection in MSM and WSM was 15.3% and 0.3%, respectively. Sixty percent of the MSM and 100% of the WSM claimed to not know of their infection. Venue-based testing may be an important strategy to identify HIV-infected younger MSM; however, other strategies are needed for WSM. Barnes W, D'Angelo L, Yamazaki M, Belzer M, Schroeder S, Palmer-Castor J, Futterman D, Kapogiannis B, Muenz L, Harris DR, Ellen JM; for the Adolescent Trials Network for HIV/AIDS Interventions. Identification of HIV-Infected 12- to 24-year-old men and women in 15 US cities through venue-based testing. Arch Pediatr Adolesc Med. 2010 Mar;164(3): 273-276.

Interventions targeting multiple risk behaviors are needed for youth living with HIV (YLH). A randomized clinical trial compared Healthy Choices, a four session motivational intervention targeting two of the three risk behaviors (HIV medication adherence, sexual risk behavior and substance use) to multidisciplinary specialty care alone. This article presents intermediary outcomes available at 3-month follow-up, variables proposed to be precursors to behavior change (motivation, self-efficacy, and depression). YLH (N=186) with at least one of the three problem behaviors were recruited from four sites in the Adolescent Trials Network for HIV/AIDS Interventions and one non-Adolescent Trials Network site, and were assessed at baseline and 3 months. Of the 94 youth randomly assigned to the treatment condition, 84% received at least one session, 67% received at least two sessions, 56% received at least three sessions, and 49% completed all four sessions. In intent-to-treat analysis, only depression was significantly improved in the treatment group as compared with controls. However, in per-protocol analysis, youth receiving at least two sessions of the intervention also showed significant improvements in motivational readiness to change as compared with youth in the control condition. Results suggest the potential benefits of clinic-based motivational interventions for YLH who access these interventions. Delivering interventions in the community using an outreach model may improve access. Analysis of subsequent time points will determine effects on actual behavior change. Naar-King S, Parsons JT, Murphy D, Kolmodin K, Harris DR and the Adolescent Trials Network 004 Protocol Team. A multisite randomized trial of a motivational intervention targeting multiple risks in youth living with HIV: initial effects on motivation, self-efficacy, and depression. J Adolesc Health. 2010 May;46(5): 422-428.

Demographic Profiles of Newly Acquired HIV Infections among Adolescents and Young Adults in the U.S.

Understanding the demographic and risk profiles of youth with recent HIV infection offers insight for imputing the dynamics of the epidemic and targeting prevention efforts. Three hundred forty-two HIV-positive youth were tested as part of the Adolescent Trials Network for HIV/AIDS Interventions (ATN) using a Sensitive/Less Sensitive strategy; 33% were classified as recently infected; with the majority male (58%), 51% African American and 26% Hispanic. There was no difference in the percent of recent vs. established cases for injection drug use (2.7% vs. 4.8%), sex while under the influence of non-injection drugs and/or alcohol (24.1% vs. 22.2%), or exchange of sex for drugs/money or given drugs/money for sex (8.9% vs. 7.8%). Among recently infected male youth 84% of all blacks, 88% of all whites, and 94% of Hispanics engaged in men-having-sex-with-men (MSM) behaviors. Of 112 recent infection cases 29% were on ARVs vs. 20% of those with established infections. Sill AM, Constantine NT, Wilson CM, Peralta L, Adolescent Trials Network for HIV/AIDS Interventions. Demographic profiles of newly acquired HIV infections among adolescents and young adults in the U.S. J Adolesc Health. 2010 Jan;46(1): 93-96.

Multiple Risk Behaviors among Youth Living with HIV

The purpose of this study was to describe multiple risk behaviors (substance use, sexual risk, and medication adherence) in a multi-site sample of youth living with human immunodeficiency virus (HIV) in five U.S. cites. Youth (N=352) were recruited from four Adolescent Trials Network (ATN) sites (Philadelphia, Fort Lauderdale, Baltimore, and Los Angeles) and one non-ATN site in Detroit and screened for multiple problem behaviors for an intervention study. A substance abuse problem was determined with the CRAFFT, a six-item adolescent screener. Single items were used to screen for current sexual risk and for an HIV medication adherence problem. Of the youth, 239 (68%) had at least one of the three risk behavior problems based on the screener. A total of 186 (52.8%) completed longer, in-depth questionnaires for each problem behavior. Of the 352 youth screened, 60% had problem level substance use and 42% had a sexual risk problem. Of the 165 (47%) who were prescribed medications, 91 (55%) reported an adherence problem. A total of 112 (32%) reported no problem behavior, 123 (35%) reported 1 problem behavior, 95 (27%) reported 2 problem behaviors, and 20 (6%) reported 3 problem behaviors. Males were more likely to have a substance use problem. Younger youth living with HIV and those perinatally infected were more likely to have an adherence problem. Among the 186 (52.8%) completing longer measures, those with a substance abuse problem had higher substance use on a timeline follow-back procedure than those without. Participants who screened positive for a sexual risk problem reported more unprotected sex on an in-depth interview than those without. Those who screened positive for an adherence problem had higher viral loads than those without an adherence problem. Results suggest high rates of problem behaviors among youth living with HIV, particularly in older youth. Younger and perinatally infected youth may require specialized adherence interventions. Associations between the screener and more in-depth assessment measures suggest potential clinical utility of screening youth for high-risk behaviors. Tanney MR, Naar-King S, Murphy DA, Parsons JT, Janisse H, ATN 004 Protocol Team. Multiple risk behaviors among youth living with human immunodeficiency virus in five U.S. cities. J Adolesc Health. 2010 Jan;46(1): 11-16.

Risks for Nonadherence to ART among Perinatally HIV Infected Youth in the U.S.

Adherence to antiretroviral regimens continues to be a significant problem in HIV-infected individuals facing a lifetime of therapy. Youth who were infected through perinatal transmission enter into adolescence often with a history of multiple medication regimens. Thus, adherence can be a particularly important issue in these young people, as medication options can often be limited. This cross-sectional, observational study was conducted as part of the Adolescent Trials Network for HIV/AIDS Interventions (ATN) to determine the prevalence of personal barriers to adherence and to identify associations among the following barriers in subjects 12 to 24 years old: mental health barriers, self-efficacy and outcome expectancy, and structural barriers. Among the 368 study participants, 274 (74.5%) were adherent and 94 (25.5%) were nonadherent to highly active antiretroviral therapy (HAART). No significant differences were found between adherent and nonadherent subjects according to mental health disorders. Adherence was associated with some but not all structural barriers. Both self-efficacy and outcome expectancy were significantly higher in adherent versus nonadherent subjects. In subjects with low self-efficacy and outcome expectancy, adherence differed according to the presence or absence of either mental health or structural barriers, similar to findings in behaviorally- infected adolescents. Interventions that address the breadth and clustering of adherence barriers in adolescents are needed to have the maximum chance for positive effects. Rudy BJ, Murphy DA, Harris DR, Muenz L, Ellen J, Adolescent Trials Network for HIV/AIDS Interventions. Prevalence and interactions of patient-related risks for nonadherence to antiretroviral therapy among perinatally infected youth in the United States. AIDS Patient Care STDS. 2010 Feb;24(2): 97-104.

Health Literacy and ART Adherence among HIV-Infected Adolescents

This study from the Adolescent Trials Network for HIV/AIDS Interventions (ATN) investigates HIV positive adolescents' health literacy and whether factors associated with health literacy in HIV-positive adults are associated with health literacy among HIV-positive adolescents. Adolescents in this study were behaviorally and perinatally HIV-infected youth (n=186) from five U.S. cities. Participants had a mean age of 20.5, and 49.5% were male. Contrary to findings for adult HIV-positive patients, among adolescents health literacy was not significantly associated with: Medication adherence adjusting for age and education level; viral load; or self-efficacy to adhere to medication regimens. The only significant association was of health literacy with medical care received. Murphy DA, Lam P, Naar-King S, Robert HD, Parsons JT, Muenz LR, Adolescent Medicine Trials Network for HIV/AIDS Interventions. Health literacy and antiretroviral adherence among HIV-infected adolescents. Patient Educ Couns. 2010 Apr;79(1): 25-29.

Predictors of Condom Use in a Multisite Study of High-Risk Youth Living with HIV

Risky sexual behavior among youth living with HIV (YLH) must be addressed in order to prevent the spread of the disease. This Adolescent Trials Network for HIV/AIDS Interventions (ATN) study investigated factors associated with condom use in a multi-site sample of YLH (ages 16-24). Baseline assessments were conducted with 186 YLH using a computer assisted personal interview (CAPI). Path analysis suggested that condom use was directly predicted by motivational readiness and self-efficacy for safer sex. Substance use was not a significant predictor of condom use. Interventions that promote self-efficacy and motivational readiness through a variety of mechanisms may be useful in understanding and conceptualizing sexual risk behavior in YLH. However, further predictors must be studied to account for more variance. Outlaw AY, Naar-King S, Janisse H, Parsons JT and the Adolescent Trials Network for HIV/AIDS Interventions. Predictors of condom use in a multisite study of high-risk youth living with HIV. AIDS Educ Prev. 2010 Feb;22(1): 1-14.

Development of Sexual and Ethnic Identity For Gay-Bisexual-Questioning Latino and African American Male Adolescents

Identity development is a critical task of adolescence and occurs across multiple areas of self-identification. Although research on the identity development process among individuals who are ethnic and sexual minorities has been conducted for individuals who have one minority status or the other, few studies have examined these processes in people who are both ethnic and sexual minorities. In this qualitative study conducted as part of intervention development work in the Adolescent Trials Network for HIV/AIDS Interventions (ATN) , the authors examined the dual identity development processes related to ethnic and sexual identity among gay-bisexual-questioning (GBQ) Latino and African American male adolescents. Results indicated that the processes associated with the development of sexual orientation and ethnic identity occur concurrently. However, the actual processes involved with the development of each identity not only differed, but seemed to be independent of each other because neither process was referenced in the development of the other. Overall, the process of ethnic identity development involved the process of becoming aware of one's ethnic and cultural heritage, whereas sexual identity development involved finding one's own personally relevant sexual orientation label and connecting to that community. The implications of these findings for the development of interventions to assist in the healthy development of GBQ adolescents are discussed. Jamil OB, Harper GW, Fernandez MI, Adolescent Trials Network for HIV/AIDS Interventions. Sexual and ethnic identity development among gay-bisexual-questioning (GBQ) male ethnic minority adolescents. Cultur Divers Ethnic Minor Psychol. 2009 Jul;15(3): 203-214.

Hepatitis B Vaccination in Urban Adolescents

Multiple studies have shown excellent response rates after hepatitis B immunization in youth; however, one previous study conducted in urban youth demonstrated poor responses. Urban youth, ages 12 to 17 years, at participating Adolescent Medicine Trials Network for HIV/AIDS Interventions Clinical/Research sites were randomized to receive either 2 doses of Recombivax HB (10 microg hepatitis B surface antigen) or Twinrix (20 microg hepatitis B surface antigen and 720 EL.U hepatitis A antigen) at 0 and 24 weeks. Safety data were collected and antibody measures performed at 0, 28, and 76 weeks. A total of 123 subjects were enrolled and 102 had week 28 serum samples available for antibody measure. A positive response (serum antibody > or =10 mIU/mL) to hepatitis B antigen was documented in 41 of 47 Recombivax HB recipients and in 52 of 55 Twinrix recipients. In an adjusted analysis, those identified as Hispanic ethnicity (N = 86) were more likely to have a positive response whereas those who identified as not heterosexual (N = 9) were less likely to respond. The majority of youth in the Twinrix arm were hepatitis A antibody positive at baseline (26/51; 51%); however, 24 of 25 hepatitis A antibody negative youth responded to the hepatitis A component. Both vaccines were safe. Response rate to 2 doses of Recombivax HB in urban youth is lower than previous studies suggest. The factors associated with diminished response are not known. Cunningham CK, Rudy BJ, Xu J, Bethel J, Kapogiannis BG, Ahmad S, Wilson CM, Flynn PM; Adolescent Medicine Trials Network for HIV/AIDS Interventions. Randomized trial to determine safety and immunogenicity of two strategies for hepatitis B vaccination in healthy urban adolescents in the United States. Pediatr Infect Dis J. 2010 Jun;29(6): 530-534.

Mobilizing Communities around HIV Prevention for Youth to Bring About Structural Changes

Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community coalitions located in Miami and Tampa, Florida, and San Juan, Puerto Rico engaged their respective communities as part of the Adolescent Trials for HIV/AIDS Interventions in bringing about structural changes affecting policies, practices and programs related to HIV prevention for 12-24-year-olds. Outcomes of this work include increased access to HIV testing and counseling in the juvenile correctional system (Miami), increased monitoring of sexual abuse between young women and older men within public housing, and support services to deter age discordant relationships (Tampa) and increased access to community-based HIV testing (San Juan). Chutuape KS, Willard N, Sanchez K, Straub DM, Ochoa TN, Howell K, Rivera C, Ramos I, Ellen JM; Adolescent Medicine Trials Network for HIV/AIDS Interventions. Mobilizing communities around HIV prevention for youth: how three coalitions applied key strategies to bring about structural changes. AIDS Educ Prev. 2010 Feb;22(1): 15-27.